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Melatonin Aids Sleep Naturally

In exciting new research in the war against insomnia and jet lag, two new studies by researchers at MIT and the Israel Institute of Technology in Haifa, have found that the natural hormone melatonin will hasten slumber quickly without the addictive effects of drugs.

The MIT study reported that melatonin, which is naturally secreted by the pineal gland in the brain, functions naturally as a sleep-inducing hormone, even when given in small doses. Dr. Richard Wurtman, professor of neuroscience at Massachusetts Institute of Technology, said "Our volunteers fall asleep in five or six minutes on melatonin, while those on placebos take 15 minutes or longer."

In the MIT study, 20 young male volunteers were given either melatonin or a placebo, and placed in a dark room at midday and told to close their eyes for 30 minutes. "In the stressful environment of having to sleep on demand, it may take volunteers 25 minutes to fall asleep on placebo and 5 or 6 minutes to get to sleep on melatonin," said Wurtman. Subjects on melatonin also slept about twice as long as those on the placebo, he said.

Dr. Wurtman also said that melatonin may be effective in treating jet lag, the effect caused when the body is taken across many time zones and endures a daylight-darkness change that disrupts sleep patterns. Wurtman said that taking melatonin at appropriate sleep times would allow the body to naturally adapt to altered day-night cycles caused by the trip.

Dr. Judith Vaitukaitis, director of the National Center for Research Resources, comments "These results will help scientists pull back the curtains that have obscured understanding of sleep." Vaitukaitis also said the MIT findings offer hope "for a natural, nonaddictive agent that could improve sleep for mil-lions of Americans."

Wurtman also said other studies have shown that older people, who often suffer from insomnia, have far less melatonin in their bodies at night than young people. "Wouldn't it be lovely if insomnia of the aged is related to the under-availability of melatonin so that tiny doses of the hormone could be used for the treatment?" said Wurtman.

In a related study, an Israeli scientist reported similar positive results using melatonin. "This is the first time that melatonin has been found to correlate with insomnia," said Dr. Peretz Lavie, Dean of Medicine at the Israel Institute of Technology in Haifa. "It works better than I dreamed possible." He reported his findings at the annual meeting of the American Sleep Disorders Association and Sleep Research Society in Los Angeles in July.

Lavie's research group first looked at melatonin levels in the blood of men and women in four categories:

  1. young adults without sleep problems;
  2. elderly people without sleep problems;
  3. elderly insomniacs who live independently, and
  4. elderly insomniacs who are institutionalized for health reasons.
The institutionalized patients had no detectable levels of the hormone during the day or night. The insomniacs who live independently had a small amount of melatonin, whereas the other groups had more or less normal levels of the hormone, Lavie said.

Insomniacs were given 2 milligrams of melatonin 2 hours before bedtime. After one week "they slept much, much better," Lavie said. Forty patients have been taking the hormone for nearly 4 months now, he said, with no ill effects. In a companion study, Lavie is giving melatonin to patients suffering from Alzheimer's disease and other dementias that severely disrupt sleep. "I can say their sleep improves enormously," he said.

Melatonin And Breast Cancer

One of the functions of melatonin-the major hormone produced by the pineal gland-appears to be to protect women against breast cancer. There is a correlation between the decline in the synthesis of melatonin with advancing age and the progressive increase in the risk of breast cancer in women. Moreover, research studies have demonstrated that melatonin can prevent chemically induced mammary tumors in laboratory rats and that the hormone can inhibit the proliferation of human breast cancer cells in tissue culture. This evidence suggests that taking supplemental melatonin may be helpful in protecting women against breast cancer, and that melatonin may also be useful in the treatment of breast cancer.

Breast cancer is the leading cause of cancer death in women in the United States and other industrialized countries. The American Cancer Society estimates that one in nine American women will become afflicted with breast cancer during their life time, and the death rate from breast cancer is rising among Americans.

There is solid evidence that taking supplemental nutrient antioxidants such as vitamin A, beta carotene, vitamin C, vitamin E, zinc, and selenium may help to protect us against the risk of cancers that are believed to be caused or exacerbated by excessive free radical activity. The evidence is especially strong that vitamin A (and related compounds) have profound anti-tumor effects, and these compounds are being studied for the treatment of several types of cancer.

It is important to understand that the word "cancer" is a generic term for a wide variety of diseases, which are all characterized by the unnaturally rapid proliferation of abnormal cells, but which are actually very different from each other. Different types of cancer have different causes, different mechanisms of action, and affect the body in a variety of ways, depending upon the virulence of disease, the tissues targeted by the disease, and the ease of rapidity by which the disease spreads (metastasizes) to other tissues within the body.

Breast Cancer And Estrogen Metabolism

There are even different types of cancer that strike the same target tissue. Breast cancer, for example, is not a single disease, and there are significant variations in its expression and development. In some women afflicted by the disease, for example, the tumor in a woman's breast develops relatively rapidly, metastasizes relatively quickly, and is almost always fatal if not treated appropriately early in its development. In other women, the breast tumor grows very slowly, attacks the body less vigorously, and can be treated more effectively at a later stage of development.

Oncologists (cancer specialists) generally agree that the most prevalent type of breast cancer is caused, in a large part, by hormonal activity involving estrogen metabolism. Although estrogen is essential for reproductive and sexual function, bone strength, and other important physiologic functions, it is also a known carcinogen. Estrogen therapy for the treatment of menopause,for example, has been linked to an increased incidence of uterine cancer, unless some type of progesterone is given to counter its carcinogenic effects. When estrogen is added to estrogen-sensitive breast tumor cells in tissue culture it stimulates the rapid proliferation of these cells. When estrogen is added to estrogen-sensitive breast tumor cells in tissue culture, it stimulates the rapid proliferation of these cells. When estrogen is given to mice and rats, it increases the incidence of mammary tumors in these animals

Melatonin Inhibits The Growth Of Breast Tumor Cells

Several groups of scientists have demonstrated that melatonin inhibits the growth of estrogen-sensitive breast cancer cells in tissue culture. The anti-proliferative effect of melatonin in breast cancer cells has been studied mostly extensively in MCF-7 breast cancer cells derived from an especially virulent type of tumor. (Hills, S.M., Spriggs, L.L., Simon, M.A., et al,. "The growth inhibitory action of melatonin on human breast cancer cells is linked to the estrogen response system", Cancer letters, 64:249-256, 1992).

In one study, concentrations of melatonin corresponding to the physiologic levels present in human blood during the evening hours (when melatonin levels rise) inhibited cell proliferation by as much as 75%, as measured by either DNA content or hemocytometer cell counts. Melatonin's inhibitory effect was reversed and the logarithmic growth of the MCF-7 breast cancer cells was restored after the tissue culture medium was replaced with fresh medium without melatonin.

This is a highly specific effect caused by melatonin. When precursors and metabolites of melatonin such as serotonin, N-acetylserotonin and 6-hydroxymelatonin are added to MCF-7 cells in tissue culture, there is no inhibitory effect on cell growth. Similarly, neither5-methoxytryptophol nor 5-methoxytryptamine, which are considered to be putative pineal hormones, exhibit this type of inhibitory effect on breast cancer growth. Only melatonin does.

How Melatonin Inhibits Breast Cancer Cell Growth

Both transmission and scanning electron microscopy have revealed the kind of morphologic changes that occur in MCF-7 breast cancer cells exposed to melatonin. After only 4 days of exposure to melatonin, MCF-7 cells exhibit reduced numbers of surface microvilli, nuclear swelling, ectoplasmic and ribosomal shedding, disruption of mitochondrial cristae vesiculation of the smooth endoplasmic reticumum, and an increase in the number of autophagic vacuoles. These striking ultrastructural changes stop the breast cancer cells from dividing, but are reversible once the cells are removed from contact with melatonin.

On the other hand, when estradiol (the most active form of estrogen) is added to MCF-7 cells in tissue culture, it stimulates cell division by including the progression of cells in the Gl resting phase to the active S phase. Estradiol can thus "rescue" breast cancer cells from a non-dividing state caused by exposure to melatonin or tamoxifen (another anti-breast cancer agent). However, when a new supply of melatonin is added to estrogen-sensitive breast tumor cells, it, once again, inhibits cell growth by increasing the fraction of cells in the Gl phase,while simultaneously causing a 50% reduction in the proportion of cells in the S phase.

Melatonin's Anti-Estrogen Effect

Scientists who have studied the effects of melatonin on breast cancer believe that the primary reason for the hormone's strong ability to inhibit the growth of MCF-7 breast cancer cells is the fact that these cells have a great number of estrogen receptors and are thus highly sensitive to estrogen stimulation. They believe that melatonin competes with estrogen for these estrogen receptors (as does tamoxifen) and, as a result, reduces the ability of estrogen to stimulate the growth of the breast cancer cells.

A recent study conducted by Steven M. Hill and associates at the Tulane University School of Medicine in New Orleans produced strong evidence that melatonin is highly effective in inhibiting estrogen-responsive breast cancers, but may be ineffective in inhibiting estrogen unresponsive breast cancers. The scientists examined the effect on cell proliferation of varying doses of melatonin added to tissue cultures containing 10 different human breast cancer cell lines.

The Tulane scientists found that the growth of all three estrogen responsive breast cancer cell lines were inhibited by melatonin. whereas melatonin had no effect (at any concentration tested) on the seven estrogen-insensitive breast cell lines. They also found that, while the MCF-7 breast cancer cells were very sensitive to the antiproliferative effects of melatonin, even in very small (nanomolar and picomolar) concentrations, the other estrogen responsive cell lines required much higher concentrations of melatonin to produce an antiproliferative effect.

Since the more resistant estrogen responsive breast cancer cell lines have far fewer estrogen receptors than the highly sensitive MCF-7 line, this suggests that there is a correlation between a tumors overall cellular responsiveness to estrogen (receptor content) and the cells' responsiveness to melatonin. This is further demonstrated by the finding that nanomolar concentrations of melatonin completely abolished the estradiol induced incorporation of radio labeled thymidine into cellular DNA within MCF-7 cells, which is a measure of the cell's proliferative capacity.

Melatonin Adds To The Potency Of Tamoxifen

Tamoxifen is a non-steroidal anti-estrogen agent, which is currently being studied as a treatment for breast cancer. Although tamoxifen is not as effective as melatonin in inhibiting the growth of MCF-7 breast cancer cells, the drug has been shown to be 100 times more effective in inhibiting cell growth if the cells have first been pre-treated with a physiologic concentration of melatonin.

In a related study, scientists at the Tumor Radiation Laboratory at the University of Milan in Italy found that elevated blood levels of melatonin markedly enhanced the responsiveness of patients to chemotherapy. The study included 42 cancer patients of both sexes, including 10 breast cancer patients, 13 lung cancer patients, and 11 colon cancer patients. It was found that 75% (12 of 16) patients whose melatonin levels were enhanced after chemotherapy exhibited objectively measured tumor regression, whereas only 8% (2 of 26 patients) whose melatonin levels did not go up after chemotherapy exhibited tumor regression.

A Regulator Of Immune And Neuroendocrine Function

The two most important regulatory systems in the body are the neuroendocrine system, which controls such essential functions as body temperature, sex drive, reproduction, appetite, sleep, balance, and muscular coordination, and the immune system, which keeps the body from succumbing to diseases triggered by bacteria, viruses, chemical pollutants, and excessive free radical activity. The pineal gland, and its primary hormone melatonin, appears to play a vital role in modulating the activity of both of these critical systems. The pineal gland translates changes in environmental lighting into neuroendocrine signals that impose a circadian rhythm upon the body which, in turn, keeps the body operating in the kind of harmonious balance characteristic of good health.

The amount of melatonin circulating in the blood has been shown to oscillate according to light signals coming in from the environment. Melatonin levels are thus relatively low during daylight hours and rise substantially during darkness, normally reaching their peak sometime after midnight. One of the keys to maintaining good health is to maintain normal, youthful patterns of melatonin secretion and activity within the body. Unfortunately, the body's supply of melatonin declines progressively with advancing age, which renders us increasingly vulnerable to physiologic malfunctions such as sleep disorders and lethal diseases such as breast cancer.

The Role Of Melatonin Secretion In Breast Cancer Patients

Studies of melatonin patterns in both healthy and diseased subjects suggest that melatonin is one of the body's first lines of defense in response to the growth of malignant breast cancer cells. It's been theorized (Relkin, R. (Ed): "The pineal and human disease", In: Annual Research Reviews, the Pineal, Lundsale House, Hornby pg. 76-79, 1986) that increased melatonin production, which activates the immune system, keeps abnormal breast cancer cells under control, but when there is inadequate (or insufficiently active) melatonin available (such as in older people) to curb the growth of these abnormal cells, very small tumors start to form in the breast. At this point-which is early in the development of the disease-its presence cannot yet be detected by manual inspection or mammography.

In response to the development of small breast tumors, the pineal gland secretes even more melatonin in an attempt to control the malignant process. When melatonin fails to control this process and primary breast cancer develops, pineal gland exhaustion sets in and the patient's blood levels of melatonin tend to decrease (especially the critical nighttime levels) as the primary tumor grows in size. (Bartsch, C., Bartsch, H., Fuchs, U., et al., "Stage-dependent depression of melatonin in patients with primary breast cancer", Cancer, 64 :426433,1989).

The decrease in blood levels of melatonin in patients with primary breast cancer is caused by a decline in the activity of serotonin-N-acetyltransferase (SNAT), the enzyme that stimulates melatonin biosynthesis, which is inhibited by alpha- and beta-adrenergic nerve fibers touching melatonin-producing cells (pinealocytes) which are, in turn, stimulated by neurons in the hypothalamic region of the brain. (Cardinali, D.P., "Neural-hormonal integrative mechanisms in the pineal gland and superiorcervical ganglia", In: Reither, R.J., Ed. The Pineal Gland, New York, Raven Press, pg. 83-107,1984).

Finally, when the primary breast tumor metastasizes and begins to spread throughout the body, the pineal gland makes a last desperate attempt (in response to new, disseminated tumor antigens) to stop the malignant process by secreting large amounts of melatonin (under the influence of alpha- and beta-adrenergic innervation) into the circulatory system. At this point, the patient's prognosis is very poor.

Occasionally, however, in some patients, the disease process can still be arrested, even at this late stage in development. Once again, one of the key factors appears to be the reserve capacity of the pineal gland. which may still revers the malignancy process if It can .continue to secrete enough high-potency melatonin. This, of course, becomes less and less possible in older breast cancer patients who suffer from progressively deteriorating pineal function caused by the aging process.

Evidence For Theraputic Role Of Melatonin In Breast Cancer Patients

Evidence for the therapeutic role of melatonin in breast cancer patients comes from a study of 25 untreated early-stage breast cancer patients by scientists in the Division of Radiation Oncology at San Gerardo Hospital in Monza, Italy. (Lissoni, P., Crispino, S., Barni, S., et al., "Pineal gland and tumor cell kinetics: serum levels of melatonin in relation to Ki-67 labeling rate in breast cancer", Oncology, 47:3:275-277, l 990). In this study, tumor cell proliferation was established by measuring Ki-67 labeling rate.

They found that patients with a negative Ki-67 labeling rate, which indicates a low rate of malignant cell proliferation, had significantly higher levels of melatonin than patients with a positive Ki-67 rate.which indicates a high rate of malignant cell proliferation. The Italian scientists concluded that: "Since tumors with high growth fraction present a worse prognosis, this study would suggest that the relief of an increased melatonin secretion represents a favorable prognostic sign, because of its association with less proliferating breast cancers."

Pineal Regulation Of Prolactin Metabolism

Another mechanism by which melatonin may act to inhibit breast tumor growth is through its regulatory control of prolactin metabolism. Prolactin is a pituitary hormone, which directly stimulates breast cancer tumor growth as well as other types of cancer, and is known to modulate the activity of gonadotrophic hormones such as estrogen. Patients with breast cancer who have depressed blood levels of melatonin also exhibit unusual prolactin secretion rhythm characterized by hypersecretion of the hormone around noon.

A study of melatonin's regulation of hormones such as estrogen, prolactin, and thyroid stimulating hormone (TSH) concluded that melatonin's ability to inhibit tumor growth "...appears to be a dynamic process with phases of inhibition and restimulation, which may be a vital part of the host-tumor interaction and help determine the course of malignant diseases including human breast cancer." (Bartsch, C., Bartsch, H. "The link between the pineal gland and cancer: An interaction involving chronobiological mechanisms" In: Halberg, F., Reale, L., Tarquini, B., Eds., Chronobiological Approach to Social Medicine, Rome: Istituto Italiano di Medicina Sociale, pg. l 05-l 26,l 984) Since melatonin is depleted not only in primary breast cancer patients, but also in patients with prostate, gastric, and colon cancer as well as in tumor-bearing animals, it may be that it plays a fundamental role in preventing different types of cancer.

Melatonin Inhibits Tumor Growth In Laboratory Rats

The anti-tumor activity of melatonin has been demonstrated in laboratory rats. In one study, daily afternoon injections of melatonin into Sprague-Dawley rats suppressed the growth and development of mammary tumors which had been induced by exposure to the carcinogen 7,l2-dimethylbenzanthracene (DMBA), while in another study, melatonin inhibited mammary tumors in rats, which had been exposed to N-nitrosomethylurea (NMU). These studies suggest that melatonin may be effective against tumors other than the estrogen-sensitive cancer lines examined in tissue culture, and that it might be effective in high doses in treating various types of human cancers.

Melatonin As A Treatment For Cancer

The idea that melatonin might be useful as an adjunct in the treatment of breast cancer (as well as in other forms of the disease) is suggested by the findings that chemotherapy is far more effective in patients whose melatonin levels are high. There have been very similar findings for thymosin, a thymic hormone that plays a vital role in immune system surveillance of abnormal cell development, and which is believed to be, in part, regulated by melatonin.

Then there is evidence (described in this article) suggesting that melatonin may be the body's first line of defense against breast cancer (and, perhaps, other cancers). What's missing are any studies reporting the clinical use of melatonin as a treatment for breast cancer, although as far back as 1956, there were reports of success in treating cancer patients with pineal extracts. (Altieri, A., Sorrentino, F., "Uber eine neue Hormontherapie des Prostatakrebses. Die Eipiphy-senextrakte", Urol Int, 2:312320, 1 956).

In the first clinical trial of melatonin as a treatment for cancer, scientists at the University of Milan in Italy gave 54 patients with metastatic solid tumors resistant to conventional therapies intramuscular injections of 20 mg. a day of melatonin. This was followed by a daily 10 mg. oral maintenance dose of melatonin in those who had responded to injections of the hormone. The subjects included patients with lung cancer, colorectal cancer, breast cancer, and other forms of the disease.

The researchers found that-in 24 of the 54 patients (33%)-melatonin -stabilized the progression of the disease and improved the quality of life in patients who had not responded to any other treatment. The disease continued to progress in the other 30 patients. (Lissoni, P., Barni, S., Cattaneo, G., et al., "Clinical Results with the Pineal Hormone Melatonin in Advanced Cancer Resistant to Standard Antitumor Therapies", Oncology, 48:448-450, 1991).

Melatonin Therapy To Prevent Cancer

There is strong evidence suggesting that healthy people should take daily doses of melatonin, in the range of 3-9 mg. per day (taken at night) as a means of protection against breast cancer, other diseases, and the ravages of aging. Melatonin has been taken in this dosage range by thousands of people without any evidence of harmful side effects. Once again, there's no proof that melatonin can help to prevent the diseases of aging, but there is a substantial amount of circumstantial evidence that maintaining normal, youthful blood levels of melatonin may be highly beneficial.

Not only has melatonin depletion (and perturbations in melatonin activity) been linked to breast cancer (and other forms of cancer), but deficiencies of melatonin have also been implicated in such diseases as cirrhosis of the liver, Klinefelter's syndrome, Cushing's syndrome, and haemochromatosis, as well as the potentially dangerous side effects of excessive exposure to artificial light, microwave radiation, and electromagnetic fields.

Health Benefits Of Melatonin

Among the health benefits of taking low doses of melatonin on a nightly basis, which have been reported both by physicians and by those taking the hormone, have been improved sleep, increased sex drive, better resistance to viral infections (as a result of improved immune function) increased energy levels, and prevention of the side effects of jet lag and other types of time disorientation. Since we started selling melatonin, we've received almost daily raves from customers telling us how much better they've been sleeping and how much better they feel since they started taking melatonin.

Because of melatonin's regulatory timing effects on the neuroendocrine and immune systems, which control virtually all our life functions, it is clearly associated with the aging process. Further evidence of melatonin's involvement with aging is its precipitous decline with advancing age, which mirrors the progressive physical and mental decline we experience as we grow older. It clearly would be wise for us to attempt to maintain youthful levels of melatonin by replacing the melatonin we lose as we grow older. Melatonin's multiple health and anti-aging benefits made it a prime candidate for an effective life extension program. As a result, we think it would be wise for everyone over the age of 30 to consider adding daily doses of melatonin to their own personal life extension program.

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